Vehicle composition containing 1-substituted azacycloheptan-2-ones

ABSTRACT

There is disclosed an improved method for topically administering a physiologically active agent to a human or animal by dissolving an effective amount of the agent in a carrier containing suitable amounts of 1-substituted-azacycloheptan-2-one, as defined herein, and contacting the skin or other membranes of the human or animal with the resulting composition, whereby penetration of the skin or membranes is enhanced.

BACKGROUND OF THE INVENTION

Many physiologically active agents are best applied topically to obtaindesirable results. Topical application, as contrasted to systemicapplication, largely avoids side effects of the agents and permits highlocal concentrations of the agents.

The greatest problem in applying physiologically active agents topicallyis that the skin is such an effective barrier to penetration. Theepidermis of the skin has an exterior layer of dead cells called thestratum corneum which is tightly compacted and oily and which providesan effective barrier against gaseous, solid or liquid chemical agents,whether used alone or in water or oil solutions. If a physiologicallyactive agent penetrates the stratum corneum, it can readily pass throughthe basal layer of the epidermis and into the dermis.

Although the effectiveness of the stratum corneum as a barrier providesgreat protection, it also frustrates efforts to apply beneficial agentsdirectly to local areas of the body. The inability of physiologicallyactive agents to penetrate the stratum corneum prevents their effectiveuse to treat such conditions as inflammation, acne, psoriasis, herpessimplex, eczema, infections due to fungus, virus or othermicroorganisms, or other disorders or conditions of the skin or mucousmembranes, or of conditions beneath the exterior surface of the skin ormucous membranes. The stratum corneum also prevents the skin fromabsorbing and retaining cosmetic-type materials such as sunscreens,perfumes, mosquito repellants and the like.

Physiologically active agents may be applied to locally affected partsof the body through the vehicle system described herein. Vehicles suchas USP cold cream, ethanol and various ointments, oils, solvents, andemulsions have been used heretofore to apply physiologically activeingredients locally. Most such vehicles are not effective to carrysignificant amounts of physiologically active agents through the skin.One such vehicle is dimethyl sulfoxide, which is described in U.S. Pat.No. 3,551,554. In this description, the term "animal" includes humanbeings as well as other forms of animal life, and especiallydomesticated animals and pets.

A number of 1-substituted-azacyclopentan-2-one compounds are known. The1-lower alkyl substituted azacyclopentane-2-ones having 1-4 carbon atomsare known to moderately enhance percutaneous absorption of chemicals,e.g., drugs. It would be desirable to obtain the same or higher level ofpercutaneous absorption with substantially lower concentrations of thepenetration-enhancing compound.

SUMMARY OF THE INVENTION

This invention is a method for carrying physiologically active agentsthrough body membranes such as skin and for retaining these agents inbody tissues. The invention also relates to compositions for use in themethod. More specifically, the invention relates to a method fortopically administering a physiologically active agent to a human oranimal comprising administering topically to a human or animal aneffective amount of a composition containing the agent and an effective,non-toxic amount of a compound having the structural formula ##SPC1##

wherein R' is H or a lower alkyl group having 1-4 carbon atoms, R is astraight or branch chain alkyl group having 1-18 carbon atoms or arylgroup, e.g., phenyl, and n is a positive integer from 0-10. In apreferred embodiment, R' is H and R is a straight chain alkyl grouphaving 1-12 carbon atoms or phenyl and n is 0-2.

It has been found that the physiologically active agents are carriedthrough body membranes by the claimed vehicles and are retained in bodytissue.

DETAILED DESCRIPTION OF THE INVENTION

Referring more particularly to the novel alkyl or aralkyl substitutedazacycloheptan-2-ones, the alkyl substituent may be straight or branchchain and has 1-18 and preferably 1-12 carbon atoms; the aralkylsubstituent is preferably benzyl.

The compounds described herein are useful in research relating topercutaneous penetration, i.e., the compounds of the present inventionenhance percutaneous absorption of topically administered chemicalagents, e.g., drugs, perfumes, dyes, insect repellants, etc.

The compound covered by the general formula above may be prepared, forexample, by treating azacycloheptan-2-one with an alkyl halide orpreferably a hydrocarbyl residue with an excellent nucleophilic leavinggroup, for example mesylate, tosylate, triflate, etc. in presence of abase in an inert atmosphere. Sodium hydride is preferred as a base. Thereaction is carried out under anhydrous conditions in a hydrocarbonsolvent, for example, dry toluene at 25°-100° C and preferably at roomtemperatures for a period of 1 to 48 hours.

In an alternate method 6-hexanolactone (ε-caprolactone) is allowed toreact with an amino-alkane over a period of 24-48 hours at 170°-250° C.

The amount of 1-substituted-azacycloheptan-2-one which may be used inthe present invention is an effective, non-toxic amount for enhancingpercutaneous absorption. Generally, this amount ranges between about 1to about 95 and preferably 5 to 40 percent by weight of the composition.

The process of this invention may find use with many physiologicallyactive agents which are soluble in the vehicles disclosed.

Fungistatic and fungicidal agents such as, for example, thiabendazole,chloroxine, amphotericin, candicidin, fungimycin, nystatin,chlordantoin, clotrimazole, ethonam nitrate, miconazole nitrate,pyrrolnitrin, salicylic acid, fezatione, ticlatone, tolnaftate, tricetinand zinc and sodium pyrithione may be dissolved in the vehiclesdescribed herein and topically applied to affected areas of the skin.For example, fungistatic or fungicidal agents so applied are carriedthrough the stratum corneum, and thereby successfully treatfungus-caused skin problems. These agents, thus applied, not onlypenetrate more quickly than when applied in the vehicles of the priorart, but additionally enter the animal tissue in high concentrations andare retained for substantially longer time periods whereby a far moresuccessful treatment is effected.

For example, the method of this invention may also be employed in thetreatment of fungus infections on the skin caused by candida anddermatophytes which cause athletes foot or ringworm, by dissolvingthiabendazole or similar antifungal agents in one of the vehicles andapplying it to the affected area.

The invention is also useful in treating skin problems, such as forexample, herpes simplex, which may be treated by a solution ofiododeoxyuridine dissolved in one of the vehicles, or such problems aswarts which may be treated with agents such as podophylline dissolved inone of the vehicles. Skin problems such as psoriasis may be treated bytopical application of a solution of a conventional topical steroid inone of the vehicles or by treatment with theophylline or antagonists ofβ-adrenergic blockers such as isoproterenol in one of the vehicles.Scalp conditions such as alopecia areata may be treated more effectivelyby applying steriods such as triamcinolone acetonide dissolved in one ofthe vehicles of this invention directly to the scalp.

The present invention is also useful for treating mild eczema, forexample, by applying a solution of fluocinolone acetonide or itsderivatives; hydrocortisone, triamcinolone acetonide, indomethacin, orphenylbutazone dissolved in one of the vehicles to the affected area.

Examples of other physiologically active steroids which may be used withthe vehicles include corticosteroids such as, for example, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorsone diacetate,flurandrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and its esters, chloroprednisone, clocortelone,descinolone, desonide, dexamethasone, dichlorisone, difluprednate,flucloronide, flumethasone, flunisolide, fluocinonide, flucortolone,fluoromethalone, fluperolone, fluprednisolone, meprednisone,methylmeprednisolone, paramethasone, prednisolone and prednisone.

This invention is also useful in antibacterial chemotherapy, e.g., inthe treatment of skin conditions involving pathogenic bacteria. Typicalantibacterial agents which may be used in this invention includesulfonomides, penicillins, cephalosporins, penicillinase, erythromycins,lincomycins, vancomycins, tetracyclines, chloramphenicols,streptomycins, etc. Typical examples of the foregoing includeerythromycin, erythromycin ethyl carbonate, erythromycin estolate,erythromycin glucepate, erythromycin ethylsuccinate, erythromycinlactobionate, lincomycin, clindamycin, tetracycline, chlortetracycline,demeclocycline, doxycycline, methacycline, oxytetracycline, minocycline,etc.

This invention is also useful in protecting ultra-sensitive skin or evennormally sensitive skin from damage or discomfort due to sunburn. Thus,dermatitis actinica may be avoided by appliction of a sunscreen, such aspara-aminobenzoic acid or its well-known derivatives dissolved in one ofthe vehicles, to skin surfaces that are to be exposed to the sun; andthe protective para-aminobenzoic acid or its derivatives will be carriedinto the stratum corneum more successfully and will therefore beretained even when exposed to water or washing for a substantiallylonger period of time than when applied to the skin in conventionalvehicles. This invention is particularly useful for ordinary suntanlotions used in activities involving swimming because the ultravioletscreening ingredients in the carriers of the prior art are washed offthe skin when it is immersed in water.

This invention may also find use in treating scar tissue by applyingagents which soften collagen, such as aminoproprionitrile orpenicillamine dissolved in one of the vehicles of this inventiontopically to the scar tissue.

Agents normally applied as eye drops, ear drops, or nose drops are moreeffective when dissolved in the vehicles of this invention.

Agents used in diagnosis may be used more effectively when applieddissolved in one of the vehicles of this invention. Patch tests todiagnose allergies may be effected promptly without scratching the skinor covering the area subjected to an allergen when the allergens areapplied in one of the vehicles of this invention.

This invention is also useful for topical application of cosmetic oresthetic agents. For example, compounds such as melanin-stimulatinghormone (MSH) or dihydroxy acetone and the like are more effectivelyapplied to skin to simulte a suntan when they are dissolved in one ofthe vehicles of this invention. The agent is carried into the skin morequickly and in greater quantity when applied in accordance with thisinvention. Hair dyes also penetrate more completely and effectively whendissolved in one of the vehicles of this invention.

The effectiveness of such topically applied materials as insectrepellants or fragrances, such as perfumes and colognes, can beprolonged when such agents are applied dissolved in one of the vehiclesof this invention.

It is to be emphasized that the foregoing are simply examples ofphysiologically active agents including therapeutic and cosmetic agentshaving known effects for known conditions, which may be used moreeffectively for their known properties in accordance with thisinvention.

In addition, the vehicles of the present invention may also be used toproduce therapeutic effects which were not previously known. That is, byuse of the vehicles described herein, therapeutic effects heretofore notknown can be achieved.

As an example of the foregoing, griseofulvin is known as the treatmentof choice for fungus infections of the skin and nails. Heretofore, themanner of delivery of griseofulvin has been oral. However, it has longbeen known that oral treatment is not preferred because of side effectsresulting from saturation of the entire body with griseofulvin and thefact that only the outer layers of affected skin need to be treated.Therefore, because fungal infections are generally infections of theskin and nails, it would be advantageous to utilize griseofulvintopically. However, despite a long-felt need for a topical griseofulvin,griseofulvin has been used orally to treat topical fungus conditionsbecause there was not heretofore known any formulation which could bedelivered topically which would cause sufficient retention ofgriseofulvin in the skin to be useful therapeutically.

However, it has now been discovered that griseofulvin, in a range oftherapeutic concentrations between about 0.1% and about 10% may be usedeffectively topically if combined with one of the vehicles describedherein.

As a further example, acne is the name commonly applied to anyinflammatory disease of the sebaceous glands; also acne vulgaris. Themicroorganism typically responsible for the acne infection isCorynebacterium acnes. Various therapeutic methods for treating acnehave been attempted including topical antibacterials, e.g.,hexachlorophene, and systemic antibiotics such as tetracycline. Whilethe systemic antibiotic treatment are known to be partially effective,the topical treatments are generally not effective.

It has long been known that systemic treatment of acne is not preferredbecause of side effects resulting from saturation of the entire bodywith antibiotics and the fact that only the affected skin need bytreated. However, despite a long-felt need for a topical treatment foracne, antibiotics generally have been used only systemically to treatacne because there was not heretofore known an antibacterial formulationwhich could be used topically which would be effective therapeuticallyin the treatment of acne. However, it has now been discovered thatantibiotics, especially those of the lincomycin and erythryomycinfamilies of antibiotics, may be used in the treatment of acne topicallyif combined with one of the vehicles described herein.

The antibiotics composition so applied is carried into and through theepidermis and deeper layers of the skin as well as into follicles andcomedones (sebum-plugged follicles which contain C. acnes) intherapeutically effective amounts and thereby successfully may be usedto temporarily eliminate the signs and symptoms of acne.

The term "physiologically active agent" is used herein to refer to abroad class of useful chemical and therapeutic agents includingphysiologically active steroids, antibiotics, antifungal agents,antibacterial agents, antineoplastic agents, allergens, antihistaminicagents, anti-inflammatory agents, ultraviolet screening agents,diagnostic agents, perfumes, insect repellants, hair dyes, etc.

Dosage forms for topical application may include solution nasal sprays,lotions, ointments, creams, gels suppositories, sprays, aerosols and thelike. Typical inert carrier which make up the foregoing dosage formsinclude water, acetone, isopropyl alcohol, freons, ethyl alcohol,polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producingmaterials, mineral oil, stearyl alcohol, stearic acid, spermaceti,sorbitan monooleate, "Polysorbates," "Tweens," sorbital,methylcellulose, etc.

The amount of the composition, and thus of the physiologically activeagent therein, to be administered will obviously be an effective amountfor the desired result expected therefrom. This, of course, will beascertained by the ordinary skill of the practitioner. Due to enhancedactivity which is achieved, the dosage of agent may often be decreasedfrom that generally applicable. In accordance with the usual prudentformulating practices, a dosage near the lower end of the useful rangeof the particular agent may be employed initially and the dosageincreased as indicated from the observed response, as in the routineprocedure of the physician.

The examples which follow illustrate the compositions of the presentinvention. Temperatures are given in degrees centigrade.

EXAMPLE 1 Preparation of 1-methyl-azacycloheptan-2-one

A suspension of 8.42 g of 57% NaH-mineral oil (4.8 g, 0.2 mole of NaH)was washed with 2 × 400 ml portions of dry toluene (distilled fromCaH₂). After the washing was completed, 350 ml of dry toluene was addedand the suspension mechanically stirred while a solution of 20 g (0.177mole) of azacycloheptan-2-one in 50 ml of dry toluene was added dropwiseover 1 hour. After the addition was completed, the mixture was refluxedwith stirring for 1 hour, then cooled to 25° C and 22.0 g (0.2 mole) ofmethyl mesylate was added dropwise over 1 hour. After the addition wascomplete, the mixture was warmed with stirring to 50° for 1 hour. Themixture was cooled, filtered and the solid was resuspended in 100 mltoluene and filtered. The combined filtrates were concentrated and theresidue was distilled at 85°-87°/0.1mm to yield 20 g (88.85%) ofproduct. On 5% SE-30 column it showed one peak.

EXAMPLE 2 Preparation of 1-octyl-azacycloheptan-2-one

The method of Example 1 is followed, except octyl mesylate was used inthe place of methyl mesylate.

Alternatively, equimolar amounts of 6-hexanolactone and n-octylaminewere heated at 190° for 20 hours. In this time, water was distilled offslowly. The residue was distilled to obtain1-octyl-azacycloheptan-2-one.

EXAMPLE 3

The following solution formulation is prepared:

    ______________________________________                                                           Solution (%)                                               ______________________________________                                        Griseofulvin         1                                                        1-octyl-azacycloheptan-2-one                                                                       10                                                       Isopropyl myristate  5                                                        Fragrance            0.1                                                      Ethanol qs. ad                                                                ______________________________________                                    

This formulation is effective in the treatment of fungus infections.

EXAMPLE 4

An aerosol form of the formulation of Example 3 is prepared by preparingthe following mixture:

    ______________________________________                                        Formulation    25%                                                            Freon.sup.1    75%                                                            ______________________________________                                         .sup.1 Freon is 75/25 Freon 114/12.?                                     

EXAMPLE 5

The following cream formulation is prepared:

    ______________________________________                                                           %                                                          ______________________________________                                        Clindamycin (base)   1.0                                                      Stearyl alcohol, U.S.P.                                                                            12.0                                                     Ethoxylated cholestrol                                                                             0.4                                                      Synthetic spermaceti 7.5                                                      Sorbitan monooleate  1.0                                                      Polysorbate 80, U.S.P.                                                                             3.0                                                      1-nonyl-azacycloheptan-2-one                                                                       20.5                                                     Sorbitol solution, U.S.P.                                                                          5.5                                                      Sodium citrate       0.5                                                      Chemoderm No. 844 Fragrance                                                                        0.2                                                      Purified water qs. ad                                                         ______________________________________                                    

This formulation is effective in the treatment of acne.

EXAMPLE 6

The following solution formulations are prepared:

    ______________________________________                                                        A(%)     B(%)                                                 ______________________________________                                        Clindamycin base   --        1.0                                              Clindamycin phosphate acid                                                                      1.3        --                                               Sodium hydroxide  0.077      --                                               1.0 Molar hydrochloric acid                                                                     --         2.27                                             Disodium edetate . 2H.sub.2 O                                                                   0.0033     0.0033                                           Fragrances        0.5        0.5                                              1-nonyl-azacycloheptan-2-one                                                                    11.0       11.0                                             Purified water    20.0       17.73                                            Isopropanol qs. ad.                                                           ______________________________________                                    

These solutions are effective for the treatment of acne in humans.

EXAMPLE 7

The following solution formulation is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        Neomycin sulfate      0.5                                                     Lidocaine             0.5                                                     Hydrocortisone        0.25                                                    1-benzyl-azacycloheptane-2-one                                                                      40.5                                                    Propylene glycol qs. ad.                                                      ______________________________________                                    

This solution is effective for the treatment of otitis in domesticanimals.

EXAMPLE 8

The following sunscreen emulsion is prepared:

    ______________________________________                                                            %                                                         ______________________________________                                        p-amino benzoic acid  2.0                                                     Benzyl alcohol        0.5                                                     1-octyl-azacycloheptane-2-one                                                                       21.0                                                    Polyethylene glycol 400-MS                                                                          10.0                                                    Isopropyl lanolate    3.0                                                     Lantrol               1.0                                                     Acetylated lanolin    0.5                                                     Isopropyl myristate   5.0                                                     Light mineral oil     8.0                                                     Cetyl alcohol         1.0                                                     Veegum                1.0                                                     Propylene glycol      3.0                                                     Purified water qs. ad                                                         ______________________________________                                    

EXAMPLE 9

The following antineoplastic solution is prepared:

    ______________________________________                                                           %                                                          ______________________________________                                        5-Fluorouracil       5                                                        1-nonyl-azacycloheptan-2-one                                                                       20.1                                                     Polyethylene glycol  5                                                        Purified water qs. ad                                                         ______________________________________                                    

EXAMPLE 10

The following insect repellant atomizing spray is prepared:

    ______________________________________                                                           %                                                          ______________________________________                                        Diethyltoluamide     0.1                                                      1-octyl-azacycloheptan-2-one                                                                       30.1                                                     Ethanol qs. ad                                                                ______________________________________                                    

EXAMPLE 11

The following lotion formulation may be prepared containing about 0.001to 1 percent, with preferably 0.1 percent fluocinolone acetonide:

    ______________________________________                                                           %                                                          ______________________________________                                        Fluocinolone acetonide                                                                             0.001 - 1                                                Cetyl alcohol        15                                                       Propylene glycol     10                                                       Sodium lauryl sulfate                                                                              15                                                       1-octyl-azacycloheptan-2-one                                                                       21                                                       Water qs. ad.                                                                 ______________________________________                                    

The steroid is dissolved in the vehicle and added to a stirred, coolingmelt of the other ingredients. The preparation is particularly usefulfor the treatment of inflamed dermatoses by topical application to theaffected skin area. The amount and frequency of application is inaccordance with standard practice for topical application of thissteroid. Penetration of the steroid into the inflammed tissue isenhanced and a therapeutic level is achieved more rapidly and sustainedfor longer duration than when the steroid is applied in conventionalformulations.

EXAMPLE 12

The percutaneous penetration of one of the claimed vehicles was comparedto a structurally related prior art vehicle by means of a diffusion cellusing excised hairless mouse skin as a membrane. Skin specimens wereobtained from male mice 14-16 weeks old. Each test solution contained 2%8-Bromo-cyclic-adenosine monophosphate and 10% phosphate buffer (0.1M;pH 6.2) and equimolar amounts of vehicle. The volume of test solutionapplied to the membrane was 0.5 Ml/cm². The results represent averagevalues obtained from 2-4 skin cells and are shown in Table 1 below.

                                      Table 1                                     __________________________________________________________________________           Penetration (hrs)                                                                      Flux    P.C.sup.3                                             Composition                                                                          25 50 75 (mole/cm.sup.2 /min)                                                                  (μcm/min)                                                                        P.R.sup.4                                       __________________________________________________________________________    A.sup.1                                                                              5  60 155                                                                              0.061   2.489 moderate                                        B.sup.2                                                                              5  65 245                                                                              0.133   5.426 moderate                                        __________________________________________________________________________

1. A: 40% 1-methyl-azacyclopentan-2-one in propylene glycol

2. B: equimolar amount of 1-methyl-azacycloheptan-2-one in propyleneglycol

3. PC: Permeability constant

4. PR: Penetration rating

I claim:
 1. A method for enhancing the penetration of physiologically active agents through human and animal body skin and membranes comprising administering to a human or animal a composition comprising an effective amount of said agent and a non-toxic, effective membrane penetrating amount of a compound having the formula ##SPC2##wherein R' is selected from the group consisting of H and alkyl having 1-4 carbon atoms, R is selected from the group consisting of an alkyl of 1-18 carbon atoms and phenyl and n is 0 or a positive integer from 1-10.
 2. The method of claim 1 wherein the physiologically active agent is an antibacterial agent.
 3. The method of claim 2, wherein the antibacterial agent is an antibiotic.
 4. The method of claim 3 wherein the antibiotic is selected from the group consisting of lincomycin, clindamycin, erythromycin and pharmaceutically useful salts thereof.
 5. The method of claim 1 wherein the physiologically active agent is a physiologically active steroid.
 6. The method of claim 1 wherein the physiologically active agent is an antifungal agent.
 7. The method of claim 1 wherein the physiologically active agent is iododeoxyuridine.
 8. The method of claim 1 wherein the physiologically active agent is a sunscreen.
 9. The method of claim 8 wherein the sunscreen is paraaminobenzoic acid or an active derivative thereof.
 10. The method of claim 1 wherein the physiologically active agent is 5-fluorouracil.
 11. The method of claim 1 wherein the physiologically active agent is an allergen. 